1 Supplementary Material for IMiC Intervention Effects Manuscript

The online supplement provides the complete analytical outputs from all stages of the study, organized into nine chapters that can be navigated via the Table of Contents on the left. Each chapter corresponds to a major component of the analysis workflow:

test 4

2 Baseline characteristics by study and intervention arm

2.1 Misame

Control
(N=73)
BEP/BEP
(N=66)
BEP/IFA
(N=56)
IFA/BEP
(N=81)
Overall
(N=276)
sex
Female 38 (52.1%) 29 (43.9%) 26 (46.4%) 46 (56.8%) 139 (50.4%)
Male 35 (47.9%) 37 (56.1%) 30 (53.6%) 35 (43.2%) 137 (49.6%)
mage
Mean (SD) 25.0 (5.28) 23.4 (5.57) 24.6 (5.56) 23.6 (5.83) 24.1 (5.58)
Median [Min, Max] 24.0 [17.0, 39.0] 22.5 [16.0, 36.0] 23.0 [16.0, 40.0] 23.0 [15.0, 39.0] 23.0 [15.0, 40.0]
meducyrs
Mean (SD) 2.66 (3.38) 2.36 (3.34) 3.07 (3.60) 3.79 (3.95) 3.00 (3.62)
Median [Min, Max] 2.00 [0, 10.0] 2.00 [0, 10.0] 2.00 [0, 10.0] 2.00 [0, 13.0] 2.00 [0, 13.0]
mhtcm
Mean (SD) 162 (6.68) 162 (5.05) 164 (6.02) 162 (5.35) 162 (5.82)
Median [Min, Max] 162 [142, 174] 162 [150, 174] 163 [151, 178] 162 [149, 173] 162 [142, 178]
parity
Mean (SD) 2.99 (1.72) 2.83 (1.71) 2.95 (1.67) 2.80 (1.76) 2.89 (1.71)
Median [Min, Max] 3.00 [1.00, 8.00] 3.00 [1.00, 7.00] 3.00 [1.00, 7.00] 2.00 [1.00, 8.00] 3.00 [1.00, 8.00]
nperson
Mean (SD) 5.92 (4.02) 6.62 (5.22) 6.88 (4.05) 6.21 (5.00) 6.37 (4.62)
Median [Min, Max] 5.00 [2.00, 23.0] 5.00 [2.00, 27.0] 6.00 [2.00, 20.0] 4.00 [2.00, 30.0] 5.00 [2.00, 30.0]
nrooms
Mean (SD) 2.37 (1.98) 2.50 (1.68) 2.46 (1.25) 2.37 (1.56) 2.42 (1.65)
Median [Min, Max] 2.00 [1.00, 12.0] 2.00 [1.00, 9.00] 2.00 [1.00, 6.00] 2.00 [1.00, 9.00] 2.00 [1.00, 12.0]
imp_water_src
Improved 41 (56.2%) 36 (54.5%) 32 (57.1%) 53 (65.4%) 162 (58.7%)
Unimproved 32 (43.8%) 30 (45.5%) 24 (42.9%) 28 (34.6%) 114 (41.3%)
impfloor
0 31 (42.5%) 25 (37.9%) 23 (41.1%) 32 (39.5%) 111 (40.2%)
1 42 (57.5%) 41 (62.1%) 33 (58.9%) 49 (60.5%) 165 (59.8%)
missing 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
cookplac
0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
missing 73 (100%) 66 (100%) 56 (100%) 81 (100%) 276 (100%)
No 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Separate space for cooking 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Yes 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
dvseason
Early Summer 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Late Summer / Monsoon 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Post-Harvest 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Post monsoon / Autumn 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Pre-Harvest 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Rainy Season 56 (76.7%) 56 (84.8%) 47 (83.9%) 63 (77.8%) 222 (80.4%)
Summer Season 17 (23.3%) 10 (15.2%) 9 (16.1%) 18 (22.2%) 54 (19.6%)
Winter 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
dlvloc
0 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
1 3 (4.1%) 1 (1.5%) 1 (1.8%) 2 (2.5%) 7 (2.5%)
3 67 (91.8%) 61 (92.4%) 52 (92.9%) 72 (88.9%) 252 (91.3%)
4 3 (4.1%) 4 (6.1%) 3 (5.4%) 7 (8.6%) 17 (6.2%)
5 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
hhwealth
Mean (SD) -0.0952 (0.987) 0.0108 (0.933) 0.250 (1.03) -0.161 (1.03) -0.0190 (1.00)
Median [Min, Max] -0.134 [-2.26, 3.04] 0.109 [-1.77, 1.86] 0.216 [-2.04, 2.34] -0.298 [-2.05, 2.64] -0.00526 [-2.26, 3.04]
hhfoodsecure
Mean (SD) 3.03 (3.20) 3.17 (2.82) 3.02 (2.86) 3.90 (3.93) 3.32 (3.29)
Median [Min, Max] 2.00 [0, 14.0] 3.00 [0, 11.0] 3.00 [0, 12.0] 4.00 [0, 14.0] 3.00 [0, 14.0]

2.2 Mumta

Control
(N=50)
BEP+ExBf
(N=50)
BEP+ExBf+AZT
(N=50)
Overall
(N=150)
sex
Female 29 (58.0%) 24 (48.0%) 31 (62.0%) 84 (56.0%)
Male 21 (42.0%) 26 (52.0%) 19 (38.0%) 66 (44.0%)
mage
Mean (SD) 24.0 (4.77) 25.2 (5.97) 23.4 (3.66) 24.2 (4.92)
Median [Min, Max] 23.0 [17.0, 35.0] 25.0 [17.0, 37.0] 24.0 [16.0, 35.0] 24.0 [16.0, 37.0]
meducyrs
Mean (SD) 7.46 (2.05) 7.96 (1.93) 8.26 (1.79) 7.89 (1.94)
Median [Min, Max] 8.00 [2.00, 14.0] 8.00 [3.00, 12.0] 8.00 [3.00, 14.0] 8.00 [2.00, 14.0]
mhtcm
Mean (SD) 153 (5.27) 151 (5.73) 153 (6.35) 152 (5.80)
Median [Min, Max] 153 [143, 165] 151 [142, 165] 153 [139, 168] 153 [139, 168]
parity
Mean (SD) 2.68 (1.78) 3.10 (2.38) 2.42 (1.36) 2.73 (1.89)
Median [Min, Max] 2.00 [1.00, 8.00] 3.00 [1.00, 12.0] 2.00 [1.00, 6.00] 2.00 [1.00, 12.0]
nperson
Mean (SD) 10.2 (3.64) 9.58 (4.44) 10.3 (4.57) 10.0 (4.22)
Median [Min, Max] 10.0 [3.00, 19.0] 9.00 [3.00, 19.0] 10.5 [3.00, 18.0] 10.0 [3.00, 19.0]
nrooms
Mean (SD) 2.74 (1.29) 2.46 (1.51) 2.58 (1.54) 2.59 (1.45)
Median [Min, Max] 3.00 [1.00, 6.00] 2.00 [1.00, 7.00] 2.00 [1.00, 6.00] 2.00 [1.00, 7.00]
imp_water_src
Improved 48 (96.0%) 47 (94.0%) 48 (96.0%) 143 (95.3%)
Unimproved 2 (4.0%) 3 (6.0%) 2 (4.0%) 7 (4.7%)
impfloor
0 1 (2.0%) 1 (2.0%) 2 (4.0%) 4 (2.7%)
1 49 (98.0%) 49 (98.0%) 48 (96.0%) 146 (97.3%)
missing 0 (0%) 0 (0%) 0 (0%) 0 (0%)
cookplac
1 (2.0%) 4 (8.0%) 3 (6.0%) 8 (5.3%)
missing 0 (0%) 0 (0%) 0 (0%) 0 (0%)
No 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Separate space for cooking 49 (98.0%) 46 (92.0%) 47 (94.0%) 142 (94.7%)
Yes 0 (0%) 0 (0%) 0 (0%) 0 (0%)
dvseason
Early Summer 4 (8.0%) 3 (6.0%) 7 (14.0%) 14 (9.3%)
Late Summer / Monsoon 15 (30.0%) 14 (28.0%) 16 (32.0%) 45 (30.0%)
Post-Harvest 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Post monsoon / Autumn 22 (44.0%) 19 (38.0%) 13 (26.0%) 54 (36.0%)
Pre-Harvest 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Rainy Season 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Summer Season 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Winter 9 (18.0%) 14 (28.0%) 14 (28.0%) 37 (24.7%)
dlvloc
0 13 (26.0%) 10 (20.0%) 16 (32.0%) 39 (26.0%)
1 3 (6.0%) 5 (10.0%) 5 (10.0%) 13 (8.7%)
3 0 (0%) 0 (0%) 0 (0%) 0 (0%)
4 32 (64.0%) 33 (66.0%) 27 (54.0%) 92 (61.3%)
5 2 (4.0%) 2 (4.0%) 2 (4.0%) 6 (4.0%)
hhwealth
Mean (SD) 0.0389 (0.862) -0.0987 (1.05) 0.0598 (1.09) 0.000000000000000137 (1.00)
Median [Min, Max] 0.0158 [-1.68, 2.09] -0.246 [-1.68, 2.13] 0.0942 [-1.68, 1.94] -0.0227 [-1.68, 2.13]
hhfoodsecure
Mean (SD) 0 (0) 0 (0) 0 (0) 0 (0)
Median [Min, Max] 0 [0, 0] 0 [0, 0] 0 [0, 0] 0 [0, 0]

2.3 Elicit

Control
(N=54)
Az.
(N=45)
Nico
(N=48)
Nico+Az.
(N=53)
Overall
(N=200)
sex
Female 26 (48.1%) 18 (40.0%) 28 (58.3%) 29 (54.7%) 101 (50.5%)
Male 28 (51.9%) 27 (60.0%) 20 (41.7%) 24 (45.3%) 99 (49.5%)
mage
Mean (SD) 30.8 (7.76) 28.5 (7.01) 28.4 (7.00) 29.5 (6.66) 29.4 (7.14)
Median [Min, Max] 31.0 [19.0, 42.0] 26.0 [18.0, 42.0] 27.0 [19.0, 46.0] 29.0 [18.0, 46.0] 28.0 [18.0, 46.0]
meducyrs
Mean (SD) 6.85 (2.59) 6.38 (2.61) 6.77 (2.43) 6.19 (2.98) 6.55 (2.67)
Median [Min, Max] 7.00 [0, 13.0] 7.00 [0, 12.0] 7.00 [0, 11.0] 7.00 [0, 13.0] 7.00 [0, 13.0]
mhtcm
Mean (SD) 158 (5.34) 157 (4.22) 158 (5.74) 158 (6.29) 158 (5.48)
Median [Min, Max] 159 [144, 168] 157 [145, 166] 158 [148, 172] 158 [143, 178] 158 [143, 178]
parity
Mean (SD) 4.89 (2.83) 3.98 (2.55) 3.92 (2.57) 4.55 (2.58) 4.36 (2.65)
Median [Min, Max] 5.00 [1.00, 12.0] 3.00 [1.00, 12.0] 3.00 [1.00, 9.00] 5.00 [1.00, 12.0] 4.00 [1.00, 12.0]
nperson
Mean (SD) 7.52 (2.49) 7.24 (2.89) 6.81 (2.88) 7.45 (2.61) 7.27 (2.70)
Median [Min, Max] 7.00 [3.00, 14.0] 7.00 [3.00, 14.0] 7.00 [1.00, 18.0] 8.00 [3.00, 14.0] 7.00 [1.00, 18.0]
nrooms
Mean (SD) 4.87 (2.18) 4.58 (2.26) 4.48 (2.13) 4.91 (2.26) 4.72 (2.20)
Median [Min, Max] 4.00 [1.00, 11.0] 4.00 [1.00, 12.0] 4.00 [2.00, 11.0] 5.00 [2.00, 12.0] 4.00 [1.00, 12.0]
imp_water_src
Improved 37 (68.5%) 30 (66.7%) 32 (66.7%) 32 (60.4%) 131 (65.5%)
Unimproved 17 (31.5%) 15 (33.3%) 16 (33.3%) 21 (39.6%) 69 (34.5%)
impfloor
0 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
1 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
missing 54 (100%) 45 (100%) 48 (100%) 53 (100%) 200 (100%)
cookplac
0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
missing 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
No 18 (33.3%) 16 (35.6%) 21 (43.8%) 21 (39.6%) 76 (38.0%)
Separate space for cooking 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Yes 36 (66.7%) 29 (64.4%) 27 (56.3%) 32 (60.4%) 124 (62.0%)
dvseason
Early Summer 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Late Summer / Monsoon 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Post-Harvest 30 (55.6%) 30 (66.7%) 28 (58.3%) 33 (62.3%) 121 (60.5%)
Post monsoon / Autumn 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Pre-Harvest 24 (44.4%) 15 (33.3%) 20 (41.7%) 20 (37.7%) 79 (39.5%)
Rainy Season 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Summer Season 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Winter 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
dlvloc
0 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
1 20 (37.0%) 22 (48.9%) 22 (45.8%) 29 (54.7%) 93 (46.5%)
3 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
4 34 (63.0%) 23 (51.1%) 26 (54.2%) 24 (45.3%) 107 (53.5%)
5 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
hhwealth
Mean (SD) -0.261 (0.611) 0.168 (1.13) -0.0165 (1.08) 0.139 (1.09) 0.0000000000000000897 (1.00)
Median [Min, Max] -0.360 [-0.807, 2.32] -0.137 [-0.807, 5.66] -0.360 [-0.807, 5.66] -0.360 [-0.851, 3.43] -0.360 [-0.851, 5.66]
hhfoodsecure
Mean (SD) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Median [Min, Max] 0 [0, 0] 0 [0, 0] 0 [0, 0] 0 [0, 0] 0 [0, 0]

3 Intervention effects forest plots and results tables

For each milk modality, the intervention effects are shown in forest plots, faceted by study and visit. Significant effects after FDR correction are shown with solid circles. Intervention average treatment effects are first shown for combined intervention arms (pooling post-natal nutritional intervention arms), and then the effects are shown contrasting each randomized arm against the control arms. Effects are estimated using TMLE, adjusting for baseline prognistic factors. Tables of results are shown below each forest plot, which also include unscaled estimates (in original units of measurement).

3.0.0.1 Macronutrients - combined arms

3.0.0.2 Macronutrients - stratified arms

3.0.0.3 Micronutrients - combined arms

Includes fat-soluble vitamins

3.0.0.4 Micronutrients - stratified arms

3.0.0.5 B-vitamins - combined arms

3.0.0.6 B-vitamins - stratified arms

3.0.0.7 HMOs - combined arms

3.0.0.8 HMOs - stratified arms

3.0.0.9 Bioactives - combined arms

3.0.0.10 Bioactives - stratified arms

4 Unadjusted estimate forest plots

For each milk modality, the intervention effects are shown in forest plots, faceted by study and visit. Significant effects after FDR correction are shown with solid circles. Intervention average treatment effects are first shown for combined intervention arms (pooling post-natal nutritional intervention arms), and then the effects are shown contrasting each randomized arm against the control arms. Effects are estimated using TMLE, unadjusted for baseline prognistic factors.

4.0.0.1 Macronutrients - combined arms

4.0.0.2 Macronutrients - stratified arms

4.0.0.3 Micronutrients - combined arms

4.0.0.4 Micronutrients - stratified arms

4.0.0.5 B-vitamins - combined arms

4.0.0.6 B-vitamins - stratified arms

4.0.0.7 HMOs - combined arms

4.0.0.8 HMOs - stratified arms

4.0.0.9 Bioactives - combined arms

4.0.0.10 Bioactives - stratified arms

5 Exploratory outcomes (microbiome, proteomics, untargeted metabolomics)

5.1 Microbiome

Intervention effects on microbiome diversity measures

Combined arms:

Stratified arms:

Intervention effects on individual microbiome components

Combined arms:

Stratified arms:

5.2 Proteomics

Note- proteomics were taken in a subset of mother-child dyads, and was only taken in the control arm of the Elicit trial, and so intervention effects were not estimatable.

No specific pattern of effects was noted, and the proportion of significant was consisten with false postives under a global null hypothesis.

5.2.1 Combined-arms

5.2.2 Arm-stratified

5.3 Untargeted Metabolomics

6 Subgroup estimates

7 Reductions in deficiency of nutrients based on MILQ standards

-below the 10th percentile -note sparse estimates -TMLE estimates -add citations -add tabulation of cutoffs (including sparse)

(Add figure legend)

8 Unscaled estimate forest plots

8.0.0.1 Macronutrients - combined arms

## Adding missing grouping variables: `measure`

8.0.0.2 Macronutrients - stratified arms

## Adding missing grouping variables: `measure`

8.0.0.3 Micronutrients - combined arms

## Adding missing grouping variables: `measure`

8.0.0.4 Micronutrients - stratified arms

8.0.0.5 B-vitamins - combined arms

## Adding missing grouping variables: `measure`

8.0.0.6 B-vitamins - stratified arms

8.0.0.7 HMOs - combined arms

## Adding missing grouping variables: `measure`

8.0.0.8 HMOs - stratified arms

8.0.0.9 Bioactives - combined arms

## Adding missing grouping variables: `measure`

8.0.0.10 Bioactives - stratified arms

9 Trajectory analyses

9.1 Tables

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9.2 Trajectory lineplots

## $p_misame_scaled

## 
## $p_elicit_scaled

## 
## $p_vital_scaled

## 
## $p_misame_unscaled

## 
## $p_misame_unscaled

## 
## $p_vital_unscaled